Abstract

Canalicular multispecific organic anion transporter (cMOAT/MRP2) is known to play a major role in the transport of anionic xenobiotics including many types of glucuronide and glutathione conjugates across the bile canalicular membrane. In the present study, the biliary excretion of telmisartan (BIBR 277) and its glucuronide was examined in Sprague-Dawley rats (SDRs) and also in mutant strain Eisai-hyperbilirubinemic rats (EHBR), which have a hereditary defect in cMOAT/MRP2. Only a minimal difference was observed in the time profile of the plasma concentration of total radioactivity after administration of an i.v. bolus of BIBR 277. About 45% of the administered dose was excreted into bile up to 240 min in both strains, most of the radioactivity in the bile being BIBR 277 glucuronide. No significant difference was observed in the biliary excretion of BIBR 277 and its glucuronide between SDRs and EHBR although the plasma disappearance of BIBR 277 glucuronide was delayed in EHBR. To explain these data, the extent of glucuronidation of BIBR 277 by liver microsomes was examined in both strains. The V_max value for the formation of BIBR 277 glucuronide was 2 to 3 times higher in EHBR than in SDRs, whereas both strains had similar K_mvalues. After an i.v. bolus administration of BIBR 277 glucuronide, its plasma disappearance was delayed in EHBR, the biliary clearance in EHBR being about half that in SDRs. These results suggest that BIBR 277 glucuronide is transported by both cMOAT/MRP2 and another transporter that is also expressed in EHBR, and that the BIBR 277 glucuronidation is enhanced in EHBR, resulting in comparable excretion of glucuronide in both strains.